Vascular remodeling is a central process in the pathogenesis of clinically important vascular diseases such as atherosclerosis, restenosis, coronary artery bypass graft failure, and arteriosclerosis that occurs in transplanted hearts and kidneys. Our published and ongoing studies indicate that Fat1, a very large atypical cadherin cell surface protein, regulates vascular smooth muscle cell growth, movement, and gene expression, key functions involved in vascular remodeling. The effect of lipids on Fat1 expression and function may reflect an important connection to clinical vascular disease. Vascular smooth muscle cells, the major structural cell type in the arterial wall, increase Fat1 expression in early phases of atherosclerotic plaque development - we postulate that this serves to maintain growth control in the stressed vascular wall. With sustained exposure to oxidized lipids, however, Fat1 expression levels fall, along with mature vascular smooth muscle cell characteristics. Our studies of vascular injury in mice lacking Fat1 specifically in this cell type show excessive growth and impaired maturation of vascular smooth muscle cells during wound healing. In addition to its expression on the cell surface, the Fat1 protein can undergo cleavage, which releases a fragment of Fat1 (the Fat1 intracellular domain) within the cell. We have found that this Fat1 fragment accumulates in the cell nucleus, where it co-operates with other factors to activate genes important for maintenance of mature vascular smooth muscle cell functions. This observation may explain how loss of Fat1 expression, as occurs with prolonged lipid exposure, is linked to the loss of mature vascular smooth muscle cell gene expression and function. These findings outline a new molecular pathway by which the Fat1 protein can relay information from the immediate environment at the surface of a cell to the cell nucleus, where the cleaved Fat1 fragment can direct gene expression and affect cellular activity. Critical points of this pathway are not yet well understood, but could serve as novel targets for therapeutic intervention in multiple vascular disease processes. Our goals under this proposal are to understand how Fat1 expression is controlled, define how Fat1 cleavage occurs, and to test the idea that Fat1 expression acts to limit vascular remodeling and associated atherosclerotic disease. PUBLIC HEALTH RELEVANCE: Vascular diseases that cause myocardial infarction, stroke, and poor circulation remain the greatest cause of death, disability, and health care expense in our society. Our work addresses novel molecular mechanisms that may govern the changes in arterial cells and artery wall structure that eventually result in atherosclerosis, vascular obstruction, and impaired blood flow, and lead to such very common diseases as angina (chest pain), heart failure, stroke, limb loss due to impaired circulation, and death. These studies in cell culture and relevant mouse models may lead to new approaches for prevention and treatment.